This is a competitive renewal of a multidisciplinary research program for the study of the clinical, communicative, neurophysiological, nutritional, epidemiologic, molecular genetic, and neuropathological aspects of Rett syndrome (RS). A variety of analytic modalities will be employed to address the fundamental mechanism(s) responsible for this disorder affecting females in early childhood. The program project consists of five projects, an administrative core, and a Design and Analysis Core. Project 1 will assess several problematic clinical features of RS which have therapeutic implications: the frequency, severity, and pattern of progression of ECG abnormalities and the possible relationship to sudden death in RS; the frequency of epileptic and non-epileptic paroxysmal events by video/EEG/monitoring versus the parental reports of seizures, the latter of which we regard as too high. Project 7 will assess energy intake and expenditure in correlation with sleep/wake cycle, heart rate variability and waking activity levels and examine responses of those to nutritional supplementation. Project 4 will continue the epidemiologic studies of the Texas RS Registry (TRSR) and the international RS survival study as well as extend the strategies of the TRSR to the state of Oregon with its significantly different demographic characteristics. Molecular genetic studies (Project 5) will extend the important observations to-date focusing on the X-chromosome with respect to translocation sites and candidate genes. Project 6 will expand the current neuropathologic observations and explore leads with regard to specific brainstem receptors, cerebral cortex morphometry, and possible mitochondrial dysfunction in muscle. Through the Design and Analysis Core, extensive networking will be developed to provide a national database for RS investigators. As stated in the previous application, this research program has evolved from the concerted efforts of clinical and basic researchers over the past eight years and represents an important opportunity to extend these collaborations.